Food effect is a well-known phenomenon that can adversely affect the pharmacokinetics of drug distribution in the body. As a result, many drugs have to be taken either in fasted or fed conditions to achieve the optimum effect. Well known examples include carbamazepine tablets (to be taken with meals), captopril tablets (to be taken one hour before meals), or azithromycin tablets (to be taken 2 hours after meal), while some other drugs remain unaffected by food, as amoxicillin for example.
For this reason, FDA recommends to test bioequivalency of drug products either under fasted or fed conditions, depending on the drug. Moreover, in the latter case the meal itself is standardized.
Little formulation work has been conducted to date in order to overcome this food effect disadvantage.
U.S. Pat. No. 5529791 describes an extended release formulation of diltiazem pellets coated with either cellulosic or synthetic polymers, and absence of food effect is reported. However, no link is explained between the composition of the product and the absence of food effect.
Benziger et al. , J. Pharm. Sci. , 85, 4, pp. 407-410 (1996) compared the bioavailability of oxycodone formulated as an immediate release aqueous solution or as extended release tablets, under fasted or fed conditions and found a significant difference in availability of the solution while no difference could be observed with the extended release tablets. These authors related the absence of food effect to the use of extended release tablets rather than to any specific formulation parameter.
U.S. Pat. No. 5,879,714 a drug and a water insoluble polymer are mixed into a molten carrier, preferably water-soluble. The only example provided in this patent consists in melting PEG 8000 at 120xc2x0 C. and dispersing nifedipine, stearic acid and Eudragit RSPO in it. After cooling, the solidified mixture is ground into granules. Heat sensitivity of many drugs seems is a major concern when considering applying the process thereto. Absence of food effect is not disclosed but it is indicated that hydrophilic matrix systems are said to be more likely to induce food effect than the disclosed formulation.
U.S. Pat. No. 5,580,578 provides controlled release formulation having a coating consisting essentially in methacrylic copolymers, said coating having been oven cured. Examples disclose compositions comprising a core comprising thee active ingredient (e.g. hydromorphone hydrochloride), an intermediate layer comprising hydroxypropylmethylcellulose and the cured overcoat based on Eudragit. After oven curing, drug products tested clinically were found to be exempt of food effect (this was however not justified by formulation parameters). The coating is comprised of sustained release acrylic copolymers of the type Eudragit RS (comprising optionally Eudragit RL).
None of the above documents teaches or suggests the present invention.
The invention relates to a novel sustained release pharmaceutical composition that is free or devoid of food effect and to a method for alleviating the food effect in the drug release.
The invention thus provides a sustained release composition free of food effect comprising:
(a) a core comprising an active ingredient; and
(b) a functional coating comprising, based on the weight of the coating, from 30 to 80% of a gastroresistant polymer and from 10 to 40% of a hydrophilic silicon dioxide.
The instant invention also provides a process for alleviating food effect in a pharmaceutical composition, comprising the step of coating a core comprising an active ingredient with a functional coating comprising, based on the weight of the coating, from 30 to 80% of a gastroresistant polymer and from 10 to 40% of a hydrophilic silicon dioxide.
The present invention consists in a coated tablet.
The core of said tablet comprises one or several pharmacologically active substances chosen among those of which absorption is known to be influenced by food intake. Examples of such drugs comprise carbamazepine, verapamil, nifedipine, felodipine, amlodipine, diltiazem, oxibutynin, doxazocin, venlafaxin, captopril, enalapril, fenofibrate, without being restricted to them.
The core usually comprises from 20 to 80% of active ingredient. It also generally comprises 10 to 80% by weight of a gelling agent, which can be chosen among hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, xanthan gum, carbomer, carragheen, polyethyleneglycol and polyethylene oxide. The core additionally comprises classical excipients, like (microcristalline) cellulose, lubricants, silicon dioxide, desintegrating agents, etc.
The core may be obtained by preparing a mixture of the starting compounds and direct compression. Alternatively, the gelling agent and the active ingredient are granulated together, and the resulting granules, optionally with other excipients, are compressed into a tablet.
Surprisingly, it has been discovered that the coating of the composition presents the unique feature of preventing the whole dosage form from being influenced by food intake.
This coating comprises a functional coating which comprises, based on the weight of the coating, from 30 to 80% of a gastroresistant polymer and from 10 to 40% of a hydrophilic silicon dioxide.
The gastroresistant polymer withstands the acidic medium of the stomach and the duodenum, but will dissolve in the intestines, as soon as the pH reaches a predetermined level (e.g. above 5.5 or above 7). This gastroresistant polymer can be selected from the group consisting in (uncured) poly(meth)acrylic acid, cellulose and alkylcellulose-phtalates. Molecular weight can vary within broad limits as will recognize the skilled man. The term xe2x80x9cuncuredxe2x80x9d is used to differentiate over U.S. Pat. No. 5,580,578.
Preferably, it is of the type of Eudragit L30D55. One preferred polymer is an anionic copolymer on the basis of methacrylic acid and acrylic acid ethyl ester. The formula is as follows: 
The ratio free carboxyl group to ester group is preferably about 1:1. The mean molecular weight is e.g. about 250,000.
Such a copolymer will easily dissolve at pH values above 5.5 with the forming of salts.
Hydrophilic silicon dioxide is a known hydrophilic anti-tacking agent, the definition of which is known to the skilled man and can be found in the literature.
The functional coating may further comprise polyethyleneglycol, present in an amount from 5 to 30% by weight, based on the total weight of the functional coating. Stearic acid, dibutyl sebacate, propylene glycol and/or triethyl citrate can used in lieu of or in addition to polyethyleneglycol.
The functional coating usually represents from 0.5 to 6% by weight of the core weight.
The composition may further comprise an intermediate coating.
This coating which acts as a protecting layer comprises classical excipients, such as those recited above with respect to the core. For example, this intermediate coating comprises hydroxypropylmethylcellulose and polyethyleneglycol. This intermediate coating usually represents from 0.1 to 3% by weight of the core weight. In the case of a layer comprised of HPMC and PEG, the weight ratio HPMC:PEG is e.g. from 2 to 10.
The composition of the invention is a sustained release; preferably it provides an effective release of the active ingredient for a period of at least 8 hours, preferably at least 12 hours.
The invention is also concerned with a process for alleviating food effect in a pharmaceutical composition, comprising the step of coating a core comprising an active ingredient with the functional coating as defined above.
Thanks to the invention, it is now possible to avoid the food effect for virtually any drug. The invention makes it possible to operate with any drug, since the process does not involve any heating step, in contrast with the prior art.
Finally, the invention concerns a composition that is the precursor of the functional coating. Thus, the invention also provides an aqueous dispersion (suspension) of a gastroresistant polymer and of a hydrophilic silicon dioxide, present according to a weight ratio gastroresistant polymer:hydrophilic silicon between 0.75:1 and 8:1.
The dispersion (suspension) typically has a solid content from 3 to 50% by weight, e.g. about 10%.
The suspension may further comprise polyethyleneglycol dissolved in it, in an amount up to 15% by weight.
One preferred embodiment is a tablet comprising:
(a) a core comprising carbamazepine;
(b) a first layer comprising HPMC and polyethyleneglycol; and
(c) a second layer comprising a methacrylic copolymer, hydrophilic silicon dioxide and polyethyleneglycol.